Duchenne Muscular Dystrophy (DMD) is the most frequent of all lethal X linked recessive disorders occurring in 1 of 3,500 boys. The disease results from the degeneration of skeletal and heart muscle as a consequence of mutations in the dystrophin gene. Typically, DMD boys have difficulty walking at an early age, become wheelchair dependent by their teen years, and die by their late 20s or early 30s. Sadly, treatment options are limited and effective therapies to curb muscle wasting and extend patient survival remains elusive. In this proposal we demonstrate that the use of a specific NFkB inhibitor compound can provide both a histological and functional improvement to skeletal muscles of mdx mice. The inhibitor is an 11 amino acid peptide, referred to as NBD, which functions by blocking the assembly of the IKK complex required for NFkB activation in response to stimuli. Treatment with NBD in young mdx mice prior to the onset of necrosis reduces macrophage infiltration and prevents myofiber lysis. Significantly, treatment of mice even in a post-necrotic phase reduces inflammation, and in addition stimulates new fiber formation. Furthermore, as described in other chronic injury models, no associated toxicity was found with NBD treatment. Together these data provide pre-clinical efficacy data that supports the use of a specific NFkB inhibitor compound for the treatment of DMD. The data further suggests that the IKK/NFkB signaling pathway is a valid therapeutic target. Indeed, we find that NFkB transcriptional activity is chronically elevated in multiple dystrophic muscles. Genetic ablation of either the transcriptionally competent p65 subunit of NFkB or the IKKbeta subunit, that is sensitive to NBD treatment, modulated the immune response and increased myogenesis in mdx mice. Based on these data, we propose that chronic activation IKK/NFkB signaling contributes to DMD pathology by functioning in both immune cells to promote necrosis and in skeletal muscle fibers to inhibit regeneration. The purpose of this proposal is to determine whether NBD treatment is efficacious in clinically relevant models of DMD. To make this determination we will perform Phase I and II pre-clinical trials using dystrophin-deficient murine and dog models of this disease. If milestones are achieved, safety studies will follow to support an IND application. Results obtained from this proposal may lead to the development of a new treatment option to improve the quality of life and/or survival of DMD patients.